Drugs acting on central nervous system - Pharmacology for Medical Graduates, 4th Updated Edition

Neurotransmitters in the central nervous system (CNS) could be inhibitory, excitatory or both ( Fig. 5.1 ).

Inhibitory postsynaptic potential (IPSP)

When an inhibitory transmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to K ⁺ or Cl ⁻ increases ( Fig. 5.2 ).

Neurotransmitters in CNS. GABA, γ-Aminobutyric acid; 5-HT, 5-hydroxytryptamine; ⊖, inhibition; ⊕, stimulation.

K ⁺ ions move out and Cl ⁻ ions move in, resulting in hyperpolarization (IPSP).

(Source: Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, p. 183, Fig. 8.3 , McGraw Hill, 2018 .)

Excitatory postsynaptic potential (EPSP)

When an excitatory neurotransmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to cations increases ( Fig. 5.3 ).

Na ⁺ ions move in (Na ⁺ influx), resulting in depolarization followed by K ⁺ efflux (EPSP).

(Source: Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, p. 183, Fig. 8.3 , McGraw Hill, 2018 .)

The phases of sleep include nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is divided into the following stages: 0, 1, 2, 3 and 4. Normally, about 50% of sleep time is spent in stage 2. Slow wave sleep includes stages 3 and 4. REM sleep constitutes about 30% of the sleep time and lasts for 5–30 minutes in each cycle of sleep.

Types of sleep disorders and their treatment are given in Table 5.1 .

• 1.

  Benzodiazepines (BZDs) *

  * Mnemonic to recollect BZDs: Sleep aids – D e L ux C ₃ OT, MAT, FaN.

  : Diazepam, lorazepam, clonazepam, clobazam, chlordiazepoxide, oxazepam, temazepam, midazolam, alprazolam, triazolam, flurazepam, nitrazepam.

• 2.

  Barbiturates:

  • Long acting : Phenobarbitone

  • Short acting : Pentobarbitone

  • Ultrashort acting : Thiopentone, methohexitone

• 3.

  Nonbenzodiazepine hypnotics: Zolpidem, zopiclone, zaleplon, eszopiclone

• 4.

  Others: Melatonin, ramelteon suvorexant

Zolpidem mainly produces hypnotic effect – decreases sleep latency and increases duration of sleep time in insomnia. It produces near-normal sleep like BZDs with minimal alteration in REM sleep; causes minimal hangover effects and rebound insomnia; less likely to produce tolerance and drug dependence; lacks anticonvulsant, antianxiety and muscle relaxant effects. It is given orally, well absorbed, metabolized in liver and excreted in urine. It has a short duration of action and is used for short-term treatment of insomnia. The actions of zolpidem are antagonized by flumazenil. The common side effects are headache, confusion, nausea and vomiting.

Mechanism of action

It is orally effective and is used for short-term treatment of insomnia. It produces near-normal sleep like BZDs. The side effects are headache, drowsiness, GI disturbances and metallic taste.

It is useful in sleep onset insomnia. It is the shortest acting non-BZD hypnotic.

It is used orally for short- and long-term treatment of insomnia.

It is a BZD analogue with hypnotic, anticonvulsant, muscle relaxant and antianxiety effects. It is useful for short-term treatment of insomnia.

It is the hormone secreted by the pineal gland; involved in the maintenance of sleep–wake cycle and circadian rhythm.

It is a melatonin-receptor (MT ₁ and MT ₂ ) agonist, can be used orally for the treatment of sleep onset insomnia. It reduces sleep latency and prolongs total duration of sleep. There is no rebound insomnia on withdrawal; does not cause tolerance on chronic use. The important adverse effects are fatigue and dizziness.

It is another melatonin-receptor agonist used for the treatment of circadian rhythm disorder in blind patients.

It prevents orexin from maintaining wakefulness by blocking orexin receptors. It is useful in chronic insomnia.

The main site of action of anaesthetics is reticular formation, which normally maintains a state of consciousness. Most anaesthetics decrease transmission in reticular formation by enhancing the activity of inhibitory transmitters like GABA (e.g. BZDs, barbiturates and propofol) and blocking the activity of excitatory transmitters (e.g. blockade of N-methyl-D-aspartate [NMDA] glutamate receptors by ketamine and nitrous oxide).

Stages of GA ( Table 5.3 ): Stages I–IV are seen mainly with ether because of its slow action. Stage II is the most dangerous period. Surgical procedures are performed in stage III. The aim of induction is to reach stage III as early as possible followed by maintenance anaesthesia and muscle relaxation.

These are discussed under the following headings ( Tables 5.4 and 5.5 ).

• 1.

  Gas/volatile liquid

• 2.

  Noninflammable/inflammable

• 3.

  Margin of safety

• 4.

  Induction and recovery

• 5.

  Skeletal muscle relaxation

• 6.

  Analgesia

• 7.

  Sensitization of myocardium

• 8.

  Hepatotoxicity

• 9.

  Irritation of respiratory passages

• 10.

  Postoperative nausea and vomiting

• 11.

  Other points

• ■

  Use of ether is obsolete.

• ■

  Halothane sensitizes the myocardium to the arrhythmogenic effect of catecholamines.

• ■

  Speed of induction and recovery depends on solubility of anaesthetic agent in blood and fat.

• ■

  Anaesthetics with low blood solubility produce rapid induction and recovery (e.g. N ₂ O and desflurane).

• ■

  Anaesthetics with high solubility in blood produce slow induction and recovery (e.g. ether).

• ■

  Desflurane, isoflurane and ether irritate respiratory passages and can induce cough.

• ■

  The basis for combining halothane/isoflurane and nitrous oxide:

  • (a)

    The concentration (MAC) of halothane/isoflurane required to produce anaesthesia is reduced when given with N ₂ O because of second gas effect. As the concentration of halothane/isoflurane required is reduced, the side effects of halothane/isoflurane (hypotension and respiratory depression) are reduced.

    • Second gas effect: N ₂ O rapidly diffuses, whereas halothane/isoflurane diffuses poorly into the blood (alveoli ↔blood ↔brain). When these (halothane/isoflurane and N ₂ O) anaesthetics are administered simultaneously, halothane/isoflurane also enters the blood rapidly along with rapidly diffusible gas (N ₂ O). This is known as ‘second gas effect’.

  • (b)

    Because of reduction in the dosage, recovery will be faster.

  • (c)

    Halothane/isoflurane is a potent anaesthetic and poor analgesic, whereas N ₂ O is a good analgesic and poor anaesthetic; hence, the combined effect of these two drugs results in potent anaesthesia and good analgesia.

• CVS: Hypotension, cardiac arrhythmias, cardiac arrest

• Respiratory depression, aspiration pneumonia, apnoea

• CNS: Convulsions, persistent sedation

• GIT: Nausea, vomiting, hepatotoxicity

• Nephrotoxicity

• Malignant hyperthermia

It is the use of drugs before administration of anaesthetics to make anaesthesia more pleasant and safe.

It is a level of CNS depression where a patient does not lose consciousness but is able to communicate and cooperate during the procedure/treatment. It is used in:

• 1.

  Uncooperative patients.

• 2.

  Anxious patients.

• 3.

  Emotionally compromised patients.

It should be avoided in chronic obstructive pulmonary disease (COPD), pregnancy, prolonged surgery, psychoses, etc. The drugs used are BZDs such as diazepam (oral, i.v.), midazolam (i.v.) and temazepam (oral); nitrous oxide + oxygen (inhalation); propofol (i.v. infusion) and fentanyl (i.v.).

LAs are weak bases. They consist of three parts: (i) hydrophilic amino group; (ii) lipophilic aromatic group; and (iii) intermediate ester or amide linkage.

Basic structure of local anaesthetics.

• 1.

  According to clinical use

  • (a)

    Surface anaesthetics: Cocaine, lignocaine, tetracaine, benzocaine, oxethazaine, proparacaine, butylaminobenzoate.

  • (b)

    Injectable anaesthetics

    • (i)

      Short acting with low potency: Procaine, chloroprocaine.

    • (ii)

      Intermediate acting with intermediate potency: Lignocaine, mepivacaine, prilocaine, articaine.

    • (iii)

      Long acting with high potency: Tetracaine, bupivacaine, dibucaine, ropivacaine.

• 2.

  According to structure

  • (a)

    Esters *

    * Note: Esters have one ‘i’; amides have two ‘i’ (i, i).

    : Coca i ne, proca i ne, chloroproca i ne, benzoca i ne, tetraca i ne.

  • (b)

    Amides * : L i gnoca i ne, mep i vaca i ne, bup i vaca i ne, pr i loca i ne, art i ca i ne, rop i vaca i ne.

LAs act on voltage-sensitive Na ⁺ channels. Sodium channels exist in resting, open and inactivated states (resting → open → inactivated state). The channels have to recover from the inactivated state to resting state before they can be opened in response to an impulse.

The LAs in ‘unionized’ form easily penetrate nerve sheath and axon membrane. Within the axoplasm, the molecules become ‘ionized’ and block the voltage-gated Na ⁺ channels.

• ■

  Blockade is frequency dependent.

• ■

  Action of LA is pH dependent and the penetrability of LA is increased at alkaline pH (i.e. when the unionized form is more). Penetrability is very poor at acidic pH of tissues. In infected tissues, there is a low pH, which causes ionization of the drug. This reduces penetration of LA through the cell membrane, thus decreases the effectiveness of LAs. Therefore, LAs are less effective in inflamed and infected areas .

• ■

  Diameter of nerve fibres: LAs block small fibres first followed by larger fibres.

• ■

  Myelinated fibres are blocked earlier than nonmyelinated nerves of the same diameter.

• ■

  Sensory fibres are blocked earlier than motor fibres because of their high firing rate and longer duration of action potential.

• ■

  Fibres in the centre are blocked later than the ones located in the circumference of the nerve bundle.

• 1.

  p K _a : Higher the p K _a , more is the ionized fraction of the drug at physiological pH. Hence, onset of action is slow and vice versa, e.g. the p K _a of procaine is 9.1. So, it has slow onset of action; whereas p K _a of lignocaine is 7.7 – it has rapid onset of action. Although p K _a of chloroprocaine is 9.1, it has a rapid onset of action.

• 2.

  Degree of plasma protein binding: Higher the plasma protein binding, longer the duration of action of the drug, e.g. procaine is poorly bound to plasma proteins, hence has a short duration of action, whereas bupivacaine is highly plasma protein bound and has longer duration of action.

• 3.

  Rate of diffusion from the site of administration: It depends on the initial concentration gradient of the drug. Higher the concentration, rapid is the onset of action.

• 4.

  Lipid solubility: Higher the lipid solubility, more is the potency of the drug, e.g. lignocaine is more potent than procaine as it is more lipid soluble.

• 5.

  Presence of vasoconstrictor: Prolongs the duration of action of LAs. The commonly used vasoconstrictor with LAs is adrenaline.

Addition of a vasoconstrictor (e.g. adrenaline) to the LA has the following advantages:

• 1.

  Slow absorption from the local site which results in prolonged duration of action of LAs.

• 2.

  Decreased bleeding in the surgical field.

• 3.

  Slow absorption of LA reduces its systemic toxicity.

Disadvantages and contraindications of combining vasoconstrictor with LA:

• 1.

  Intense vasospasm and ischaemia in tissues with end arteries may cause gangrene of the part (e.g. fingers, toes, penis, ear lobule and tip of the nose). Hence, use of vasoconstrictors is contraindicated in these sites.

• 2.

  Absorption of adrenaline can cause systemic toxicity – tachycardia, palpitation, rise of BP and precipitation of angina or cardiac arrhythmias. Hence, combined preparation (LA with adrenaline) should be avoided in patients with hypertension, congestive cardiac failure (CCF), arrhythmias, ischaemic heart disease and uncontrolled hyperthyroidism.

• 3.

  May delay wound healing by reducing the blood flow to the affected area.

• 1.

  Nervous system

  • (a)

    Peripheral nerves: Autonomic fibres are blocked earlier than somatic fibres. Sensation of pain disappears first followed by temperature, touch, pressure and motor functions.

  • (b)

    CNS : Most of the LAs cross the blood–brain barrier (BBB) – initially they cause CNS stimulation and then depression in higher doses. They cause excitement, tremor, twitching, restlessness and convulsions. Large doses can cause respiratory depression, coma and death.

• 2.

  Cardiovascular system

  • (a)

    Heart: LAs, by blocking Na ⁺ channels, decrease abnormal pacemaker activity, contractility, conductivity, excitability, heart rate, cardiac output and increase effective refractory period.

    • (i)

      At higher concentrations, i.v. administration of LAs may precipitate cardiac arrhythmias.

    • (ii)

      Bupivacaine is more cardiotoxic than other LAs – may cause cardiovascular collapse and death.

    • (iii)

      Lignocaine decreases automaticity and is useful in ventricular arrhythmias.

  • (b)

    Blood vessels: LAs produce hypotension due to vasodilatation and myocardial depression.

Most of the ester-linked LAs are rapidly metabolized by plasma cholinesterase, whereas amide-linked drugs are metabolized mainly in liver. LAs (procaine, lignocaine, etc.) are not effective orally because of high first-pass metabolism. In liver diseases, the metabolism of lignocaine may be impaired; hence, dose must be reduced accordingly.

Comparative features of esters and amides are shown in Table 5.6 .

• 1.

  CNS: LAs initially cause CNS stimulation followed by depression. They are restlessness, tremor, headache, drowsiness, confusion, convulsions followed by respiratory depression, coma and death.

• 2.

  CVS: Bradycardia, hypotension, cardiac arrhythmias and rarely cardiovascular collapse and death. Bupivacaine is highly cardiotoxic.

• 3.

  Allergic reactions: These are skin rashes, itching, erythema, urticaria, wheezing, bronchospasm and rarely anaphylactic reaction. The incidence of allergic reactions is more with ester-linked LAs than with amide-linked LAs.

• 4.

  Mucosal irritation (cocaine) and methaemoglobinaemia (prilocaine) may be seen.

• 5.

  Methylparaben, preservative in LA preparation, may cause allergic reaction.

  • Important properties of LAs are given in Table 5.7 .

    Table 5.7 ■

    Properties of local anaesthetics

    Drug	Group	Duration of action (minutes)	Potency	Onset	Tissue penetrability	Other points
    Procaine	Ester	15–30 (short)	Low	Slow	Poor	No surface anaesthesia
    Chloroprocaine	Ester	15–30 (short)	Low	Rapid	–	–
    Tetracaine	Ester	120–240 (long)	High	Very slow	Moderate	• Widely used in spinal and corneal anaesthesia • High systemic toxicity because of slow metabolism
    Cocaine	Ester	–	–	Intermediate	Good	• Inhibits the reuptake of NA in both central and peripheral nerves • Causes tachycardia, rise in BP, mydriasis and euphoria • Rarely used
    Lignocaine	Amide	30–60 (intermediate)	Intermediate	Rapid	Good	Most widely used local anaesthetic; also used in ventricular arrhythmias
    Mepivacaine	Amide	45–90 (intermediate)	Intermediate	Intermediate	–	No surface anaesthesia
    Bupivacaine	Amide	120–240 (long)	High	Intermediate	Moderate	Highly cardiotoxic, widely used for spinal, epidural, infiltration and nerve block – because of long duration of action; low concentration used for epidural analgesia during labour
    Ropivacaine	Amide	120–360 (long)	Intermediate	Intermediate	Moderate	Similar to bupivacaine, less cardiotoxic
    Prilocaine	Amide	Intermediate	–	Intermediate	Moderate	Widely used; can cause methaemoglobinaemia
    Dibucaine	Amide	180-600 (long)	High	Slow	Good	Useful as topical anaesthetic for anal mucous membrane
    Articaine	Amide	60	–	Rapid	–	Used for infiltration and nerve block anaesthesia; can cause methaemoglobinaemia, paraesthesia and neuropathy

    Note: NA, noradrenaline.

• 6.

  Adverse effects due to the use of vasoconstrictor (see p. 183)

• 1.

  Antiseptic: 70% ethyl alcohol is used as an antiseptic on skin before giving injection and surgical procedure. Its antiseptic efficacy decreases above 90%. It should not be used on open wounds, mucosa, ulcers and on scrotum as it is highly irritant. It is not useful for disinfecting instruments as it promotes rusting.

• 2.

  Trigeminal and other neuralgias: Injection of alcohol directly into nerve trunk relieves pain by destroying them.

• 3.

  Prevent bedsores: Alcohol is used locally to prevent bedsores in bedridden patients.

• 4.

  Methanol poisoning: Ethanol competes with methanol for metabolic enzymes and saturates them. Hence, it prevents the formation of toxic metabolites of methanol (formaldehyde and formic acid).

• 5.

  Fever: Alcoholic sponges are useful to reduce body temperature.

This occurs when methylated spirit is consumed or when liquor is adulterated with methyl alcohol. Methanol is a mild CNS depressant. It is metabolized to formaldehyde and formic acid which, in turn, cause metabolic acidosis and injury to retina. The signs and symptoms of methanol poisoning are nausea, vomiting, abdominal pain, headache, vertigo, confusion, hypotension, convulsions and coma. Metabolic acidosis is due to formic acid which also causes dimness of vision, retinal damage and blindness.

• 1.

  Generalized tonic–clonic seizures (GTCS, grand mal epilepsy): It is characterized by the following sequence of symptoms: Aura–epileptic cry–loss of consciousness–fall to the ground–tonic phase–clonic phase–period of relaxation–postepileptic automatism with confusional states.

• 2.

  Absence seizures (petit mal epilepsy): It is characterized by sudden onset of staring, unresponsiveness with momentary loss of consciousness.

• 3.

  Myoclonic seizures: It consists of single or multiple sudden, brief, shock-like contractions.

• 1.

  Simple partial seizures (SPS): The manifestations depend on the region of cortex involved. There may be convulsions (focal motor symptoms) or paraesthesia (sensory symptoms) without loss of consciousness.

• 2.

  Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor epilepsy): It is characterized by aura–amnesia–abnormal behaviour and automatism with impaired consciousness.

• 1.

  Hydantoins: Phenytoin, fosphenytoin.

• 2.

  Barbiturate: Phenobarbitone.

• 3.

  Iminostilbenes: Carbamazepine, oxcarbazepine.

• 4.

  Carboxylic acid derivatives: Sodium valproate, divalproex.

• 5.

  Succinimide: Ethosuximide.

• 6.

  BZDs: Lorazepam, diazepam, clonazepam, clobazam.

• 7.

  Others: Lamotrigine, topiramate, gabapentin, pregabalin, tiagabine, vigabatrin, zonisamide, levetiracetam, lacosamide.

The classification of antiepileptic drugs is presented in Table 5.9 .

It is a medical emergency and should be treated immediately. It is characterized by recurrent attacks of tonic–clonic seizures without the recovery of consciousness in between or a single episode lasts longer than 30 minutes.

• 1.

  Opioid agonists

  • (a)

    Natural opium alkaloids: Morphine, codeine, thebaine,* papaverine,* noscapine.*

  • (b)

    Semisynthetic opiates: Heroin, pholcodine,* hydromorphone, oxymorphone.

  • (c)

    Synthetic opioids: Pethidine, tramadol, tapentadol, methadone, dextropropoxyphene, fentanyl, alfentanil, sufentanil, remifentanil.

• 2.

  Opioid agonist–antagonists: Pentazocine, butorphanol, nalorphine, nalbuphine.

• 3.

  Partial μ-receptor agonist and κ-receptor antagonist: Buprenorphine.

Note: *Have no analgesic activity.

The three main types of opioid receptors are μ (mu), κ (kappa) and δ (delta). These receptor-mediated effects are given below.

• μ: Analgesia (spinal + supraspinal level), respiratory depression, dependence, sedation, euphoria, miosis, decrease in GI motility.

• κ: Analgesia (spinal + supraspinal level), respiratory depression, dependence, dysphoria, psychotomimetic effect.

• δ: Analgesia (spinal + supraspinal level), respiratory depression, proconvulsant action.